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We hypothesized that the epithelial reticular basement membrane (RBM) thickening and eosinophilic inflammation characteristic of asthma would be present in symptomatic infants with reversible airflow obstruction.RBM thickness and numbers of inflammatory cells were determined in ultrathin sections of endobronchial biopsies obtained from 53 infants during clinical bronchoscopy for severe wheeze and/or cough. Group A: 16 infants with a median age of 12 months (range 3.4-26 months), with decreased specific airway conductance (sGaw) and bronchodilator reversibility; Group B: 22 infants with a median age of 12.4 months (5.1-25.9 months), with decreased sGaw but without bronchodilator reversibility; and Group C: 15 infants with a median age of 11.5 months (3.4-24.3 months) with normal sGaw. Additional comparisons were made with the following groups. Group D: 17 children, median age 10.3 years (6-16 years), with difficult asthma; Group E: 10 pediatric control subjects without asthma, median age 10 years (6-16 years); and Group F: nine adult normal, healthy control subjects, median age 27 years (21-42 years).There were no significant differences in RBM thickness or inflammatory cell number between the infant groups. RBM thickness was similar in the infants and Groups E and F. However, the RBM in all infant groups (Group A: median 4.3 microm [range 2.8-9.2 microm]; Group B: median 4.15 microm [range 2.7-5.8 microm]; Group C: median 3.8 microm [range 2.7-5.5 microm]) was significantly less thick than that in the older children with asthma (Group D: median 8.3 microm [range 5.3-12.7 microm]; p0.001).RBM thickening and the eosinophilic inflammation characteristic of asthma in older children and adults are not present in symptomatic infants with reversible airflow obstruction, even in the presence of atopy.

Sensory neuropeptides are localized to airway nerves and endocrine cells in both human and animal species and may participate in the development of airway inflammation and hyperresponsiveness (AHR). We used a mouse model to identify the changes that occur in calcitonin gene-related peptide (CGRP) expression in the airways during development of allergic inflammation and to investigate the potential role of this neuropeptide in modulating AHR. In sensitized mice, allergen challenge induced eosinophilic airway inflammation and AHR and resulted in considerable depletion of CGRP in neuroepithelial bodies and submucosal nerve plexuses without altering the overall density of airway nerve fibers. This depletion was subsequent to the development of airway inflammation and was prevented by anti-very late antigen-4 and anti-interleukin-5 treatments, which blocked airway eosinophilia and abolished AHR. Administration of CGRP to sensitized and challenged mice resulted in the normalization of airway responsiveness to inhaled methacholine, an effect that was neutralized by the receptor antagonist CGRP(8-37). These data demonstrate that replacement of CGRP following its depletion in allergic mice can reverse the changes in airway responsiveness and suggest that CGRP may have potential for the treatment of allergic AHR.

Tumor necrosis factor (TNF)- α is a potent cytokine with immunomodulatory, proinflammatory, and pathobiologic activities. Although TNF- α is thought to play a role in mediating airway inflammation and airway hyperresponsiveness (AHR), its function is not well defined. TNF- α –deficient mice and mice expressing TNF- α in their lungs because of a TNF- α transgene placed under the control of the surfactant protein (SP)-C promoter (SP-C/TNF- α –transgenic mice) were sensitized to ovalbumin (OVA) and subsequently challenged with OVA via the airways; airway function in response to inhaled methacholine was monitored. In the TNF- α –deficient mice, AHR was significantly increased over that in controls. In contrast, the transgenic mice failed to develop AHR. In addition, sensitized/ challenged TNF- α –deficient mice had significantly increased numbers of eosinophils and higher levels of interleukin (IL)-5 and IL-10 in their bronchoalveolar lavage fluid than were found for control mice. However, in SP-C/TNF- α –tra...

In mice, respiratory syncytial virus (RSV) infection can enhance the consequences of allergic airway sensitization, resulting in lung eosinophilia and the development of airway hyperresponsiveness (AHR) to inhaled methacholine (MCh). To delineate a role for interleukin-5 (IL-5), interleukin-4 (IL-4), and interferon gamma (IFN-gamma) in mediating the effects of RSV infection on subsequent allergic sensitization, we treated BALB/c mice with anti-IL-5 during acute RSV infection but not during subsequent exposure to ovalbumin (OVA). IL-5-deficient and IL-4-deficient mice were also treated with IL-5 either during acute RSV infection or during the sensitization period. Airway responsiveness to inhaled MCh was assessed and numbers of lung eosinophils were monitored. Anti-IL-5 treatment during RSV infection reduced AHR and lung eosinophilia after subsequent exposure to allergen. In IL-5-deficient or IL-4-deficient mice lung eosinophilia and AHR after RSV infection and allergen exposure were also markedly reduced. IL-5 administration during RSV infection restored the responses to allergen in both IL-5- and IL-4-deficient mice. However, IL-5 administration only during sensitization restored these responses in IL-4-deficient but not in IL-5-deficient animals. IFN-gamma-deficient mice developed AHR and some lung eosinophilia after allergen exposure alone and when RSV infection preceded allergen, these responses were enhanced. We conclude that both IL-5, particularly during acute infection, and IL-4 are critical in mediating the effects of RSV infection on allergic airway sensitization, resulting in the development of AHR and lung eosinophilia.